In a First, Scientists Precisely Edit Human Embryo Genes

Scientists at Columbia University have edited the DNA of early human embryos with unprecedented accuracy, an achievement that could open the way to babies engineered with particular characteristics.

The prospect has fueled controversy for years. On the one hand, the technology might one day enable parents to safely repair disease-causing mutations in embryos. But it might also be used to select desired traits — a practice that some ethicists have argued is nothing short of eugenics.

Dieter Egli, a geneticist at Columbia University who led the research, called for a public conversation about the pros and cons of altering embryonic DNA. “As a scientist, you can provide the data for discussion, but then essentially there you stop and let others take over,” he said.

With a newer technology called base editing, Dr. Egli and his colleagues were able to meticulously replace individual genetic letters in sequences of DNA without causing the damage often observed with an earlier form of gene editing, CRISPR.

Dr. Egli cautioned that the research left unanswered many questions about harmful side effects. “We’re not saying this is going to be used tomorrow in the clinics,” he said.

Dr. Egli and his colleagues posted their study online. The research is under review for publication in a scientific journal.

The possibility of editing the DNA of human embryos became a matter of serious debate more than a decade ago, after the invention of CRISPR.

In 2012, scientists discovered how to create customized molecules that could snip out a targeted segment of DNA. CRISPR quickly became a standard tool for scientists — a cheap, easy way to discover how genes function by tweaking the genome.

A number of medical companies sprang up, seeking to use the technology to treat hereditary diseases. In 2023, the Food and Drug Administration approved a CRISPR-based treatment for sickle cell anemia.

But scientists knew it was not perfect. In some cells, CRISPR molecules failed to find their targets in DNA, or sometimes snipped out the wrong genetic bits.

Those concerns did not stop a Chinese scientist, He Jiankui, from using CRISPR to alter the DNA of human embryos in 2018.

Dr. He later said his goal was to give children a genetic resistance to H.I.V. infection. But experts condemned his work as reckless, and Chinese authorities imprisoned him for three years.

Dr. He’s experiment led to three “healthy, beautiful babies,” he claimed in a January interview with The New York Times. But the status of the children has never been independently evaluated.

In 2020, Dr. Egli and his colleagues carried out an experiment to see how CRISPR behaves in human embryos.

They obtained donated sperm from men with a mutation in a gene called EYS causing hereditary blindness. The researchers used the sperm to fertilize healthy eggs, producing human embryos with one working copy of EYS and one defective copy. The researchers used CRISPR to cut out the mutant region of EYS.

Previous studies suggested that the embryo might repair the gene by using the healthy version as a guide. Only some embryos did so, ending up with two working copies of EYS.

But the repair failed in about half of them. Some chopped off long stretches of DNA. Some destroyed the entire chromosome on which the EYS gene is located.

“It had absolutely catastrophic consequences,” Dr. Egli said.

Many scientists and bioethicists saw these results as further evidence that editing human embryos was far too risky to even consider — at least, for the time being.

But in 2016, David Liu, a geneticist at Harvard University, and colleagues combined one of the CRISPR molecules with other compounds to create base editing, a new method for editing genes. Rather than chop out a segment of DNA, base editors made a tiny nick in one strand. They could then guide the cell to fix the mutation.

Base editing has proved to be often superior to earlier CRISPR methods. Last year, a baby was cured of a potentially lethal genetic disorder after receiving a customized set of base editing molecules.

Dr. Egli decided to try it on human embryos.

For the new experiments, he and his colleagues set out to alter two genes. One, called PCSK9, can carry mutations that raise levels of LDL in the blood — and the risk of heart disease. The other gene, HBG, directs hemoglobin production in fetuses.

Dr. Egli and his colleagues delivered their base editors into fertilized eggs and into two-cell embryos donated by parents. The researchers didn’t find any of the extensive damage associated with CRISPR.

Instead, the researchers were able to successfully change both the PCSK9 and HBG genes. In some experiments, they simultaneously changed both genes in the same embryo.

But the edits were still not perfect. Sometimes the base editing molecules failed to find their target DNA. As a result, some cells in the embryos retained the original versions of the genes, while others were altered.

Those embryos became genetic mixtures, so-called mosaics. Having cells with different versions of the same gene could have led to medical problems had the embryos developed into babies.

Despite those failures, the new results were strong enough that Dr. Paula Amato, a fertility expert at Oregon Health & Science University who was not involved in the study, thought the method was “promising.”

Still, she said it would be important to examine the final results when they’re published in a journal.

Ana Iltis, a bioethicist at Wake Forest University, worried that assessing the safety of base-edited embryos will require far more scrutiny than simply looking for damaged chromosomes.

“It is possible that some of the potentially harmful effects would not be evident until after birth,” she warned.

Nathan Treff, the chief clinical officer of Nucleus Genomics and a co-author of the new study, said that the ability to fix disease-causing mutations in embryos could be a boon to those using I.V.F., allowing them to implant embryos that they otherwise would have discarded.

“There’s still work to do before getting to that point, but this research gets us closer,” Dr. Treff said.

Nucleus Genomics will support the next stage of Dr. Egli’s research. (The federal government does not fund studies on human embryos for research purposes.)

Some upcoming studies will look for ways to avoid mosaic embryos. The researchers will also test base editing on embryos that contain about 100 cells. Fertility clinics typically freeze and test embryos at that stage.

Nucleus Genomics, founded in 2021, screens I.V.F. embryos for thousands of genetic disorders. The company also makes predictions about an embryo’s risks for conditions such as heart disease and diabetes. And it looks at genes linked to traits such as height and intelligence.

In November, the firm stirred controversy when it plastered ads on New York City subways telling commuters to “have your best baby.” Geneticists have criticized the predictions Nucleus Genomics makes for traits, such as IQ, as having low accuracy.

And critics have accused the company of promoting a biotech spin on eugenics — a charge the company rejects.

“We see ourselves as a natural pathway for eventually bringing technologies like this into clinical care as part of a broader genetics platform — a full ‘Genetic Optimization’ stack,” Kaitlyn Gallacher, head of communications at Nucleus Genomics, wrote in an email.

Fyodor Urnov, a geneticist at the University of California, Berkeley, who was not involved in the study, said the results were in line with earlier studies of base editing in living cells.

But the prospect of using the method on embryos was both novel and risky, Dr. Urnov said. In regular I.V.F., embryos are screened for genetic abnormalities. That made much more sense, he argued, than resorting to a new technique with so many open questions.

“Do we do what we’ve done safely and effectively 15 million times since 1978, or do we instead try something that we can never truly de-risk, and where the risks are clear?” he asked.

Dr. Urnov speculated that the new method, once perfected, would appeal to people who don’t merely want to address inherited diseases, but to enhance traits by engineering embryos.

“What they are really doing is providing the ‘baby improvers’ with a how-to manual for forays beyond the ethical pale,” Dr. Urnov wrote in an email.

Whether anyone could actually alter babies in this way is not yet settled, though. Many human traits are influenced by hundreds, or thousands, of genes.

Dr. Egli noted that the more genes in a single embryo that scientists try to rewrite, the higher the risk that they will fail.

“I think you can probably combine three or four, maybe even five, but I think there’s a limit,” he said. “Where that limit is remains to be determined.”